Toxicology of human medications (Proceedings)

Article

Selective serotonin reuptake inhibitors (SSRIs) all differ structurally, but have the same ability to inhibit presynaptic neuronal reuptake of serotonin.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) all differ structurally, but have the same ability to inhibit presynaptic neuronal reuptake of serotonin. Drugs in this class include fluoxetine (Prozac®, Sarafem®), paroxetine (Paxil®), sertraline (Zoloft®), fluxovamine (Luvox®), citalopram (Celexa®) and escitalopram (Lexapro®). They have little to no effect on non-serotonin neurotransmitters and thus have less anticholinergic, sedative and cardiovascular side effects than other types of antidepressants.

All SSRIs are well absorbed and are highly protein bound. The SSRIs are metabolized in the liver and eliminated in the urine and/or feces. The most common signs of overdose are depression, vomiting, anorexia, ataxia, muscle tremors, arrhythmia (tachycardia and bradycardia are possible), and hypertension. Serotonin syndrome may be seen in some cases, especially when SSRIs are ingested with MAO inhibitors. The term serotonin syndrome has been used to describe multiple signs associated with severe SSRI toxicosis, including agitation, tremors, tachycardia, and hyperthermia. Other less common signs include diarrhea, salivation, mydriasis, seizures, nystagmus, and coma. Hypotension and hyponatremia have been reported in humans.

Emesis should only be attempted with recent exposures, assuming that the patient is asymptomatic. Gastric lavage may be considered if large numbers of pills were ingested. Activated charcoal with a cathartic should be administered and may be effective several hours after exposure. It is thought that repeat doses of activated charcoal may be effective in SSRI elimination.

Treatment consists of monitoring vital signs closely, controlling clinical signs and providing appropriate supportive care. Diuresis does not enhance excretion because SSRIs are highly protein bound, but fluid therapy should be considered to help support blood pressure and maintain renal function. Diazepam can be used to control seizures and treatment of CNS signs may also help in the control of some of the other signs such as tachycardia, hypertension, and hyperthermia. Propranolol is a serotonergic receptor antagonist and may be used to counter tachycardia. Cyproheptadine, in addition to being an antihistamine and an appetite stimulant, is a non-selective serotonin reuptake inhibitor and has been useful in the treatment of serotonin syndrome (dog 1.1 mg/kg; cat 2 to 4 mg). Cyproheptadine may be crushed in saline and given rectally if vomiting is a problem. Chlorpromazine or acepromazine can be used in addition to cyproheptadine to treat agitation.

Venlafaxine

Venlafaxine (Effexor®) is a bicyclic antidepressant; it is a potent serotonin and noradrenaline reuptake inhibitor as well as a weak dopamine reuptake inhibitor. It is available as both an immediate release and extended release medication. While it is rare for cats to willingly ingest medications, cats and dogs seem to readily eat venlafaxine. Mydriasis, vomiting, tachypnea, tachycardia, ataxia and agitation are the most common signs. Treatment would consist of emesis in asymptomatic individuals. Activated charcoal can be administered with a repeated dose in 4-6 hours if an extended release formulation was involved. Heart rate and blood pressure should be monitored. Acepromazine may be used for the agitation, and cyproheptadine may be useful in antagonizing the serotonin effects.

With ingestion of the extended release medication, cats can be symptomatic for up to 72 hours. Venlafaxine is lipid soluble, so intralipids can be used to decrease plasma levels and decrease treatment time. Liposyn, or any other 20% lipid solution can be given through a peripheral catheter. A bolus of 1.5 ml/kg is given, followed by 0.25 ml/kg/min for 30-60 minutes. This is repeated in four hours if the serum is clear. As an aside, venlafaxine will cause a false positive reaction for PCP on the OTC urine drug tests.

Albuterol

Albuterol (Proventil®, Ventolin®) is a synthetic sympathomimetic amine with primarily beta-2 receptor agonist properties. It is used most commonly for the treatment of asthma. Albuterol binds to beta-2 receptors on the surface of the smooth muscle cells in many different tissues as well as in skeletal muscle, liver and cardiac tissue. Binding to the receptor initiates the conversion of ATP to cyclic AMP, which mediates a variety of intercellular responses resulting in smooth muscle relaxation, increased skeletal muscle contractility and an intracellular shift of potassium. Overdoses of albuterol may lead to effects of beta-1 stimulation, including increased inotropic and chronotropic effects on the heart.

Dogs are usually exposed by chewing on inhalers but there are also solutions, syrups, powders, tablets, and extended release tablets available. When inhalers are punctured, dogs get an inhalation plus an oral exposure. This leads to a quick onset of signs and prolonged duration signs. When inhaled, signs can begin in five minutes. Ingestions usually have a lag time of 30 minutes before clinical signs start. In dogs, signs generally resolve within 12 hours except for certain individuals who may experience signs for up to 48 hours. The most common signs seen are tachycardia, vomiting, depression, tachypnea, hyperactivity, muscle tremors, hypokalemia, and weakness. Rarely, death has been reported.

Decontamination is not advised for inhaler, solution or syrup exposure due to rapid absorption and onset of actions. Emesis (if within minutes of ingestion) and activated charcoal advised with tablet ingestion only (especially extended relief tablets). Vital signs, heart rate and rhythm, and serum potassium levels should be monitored closely for at least the first 12 hours post-exposure and longer if clinical signs persist.

Propranolol or other non-selective beta blockers should be administered if heart rates greater than 160 to 180 bpm are observed. Propranolol slows the heart rate, has direct myocardial depressant effects and helps normalize serum potassium levels. Potassium may be supplemented as needed and should be considered if serum potassium levels fall below 2.5 mEq/l. Animals with known or underlying cardiac disease may be at risk for decompensation and sudden death. Agitation can be treated with diazepam or low dose acepromazine. Prognosis in most cases is very good.

Amphetamines and related compounds

Amphetamines can be found in both prescription ADHD and weight loss medications (Ritalin®, Adderall®, Vyvanse®, Concerta®), as well as illicit substances (methamphetamine, crack). Pseudoephedrine is a common component of many cold and allergy medications. Pharmacologically, amphetamines and pseudoephedrine are sympathomimetic alkaloids. The alkaloids stimulate alpha- and beta-adrenergic receptors, causing the release of endogenous catecholamines at synapses in the brain and heart. This stimulation causes peripheral vasoconstriction and cardiac stimulation resulting in hypertension, tachycardia, ataxia, restlessness, tremors, and seizures. Because signs can occur as early as 15-30 minutes of ingestion, decontamination at home is often not recommended. With ingestions of extended release forms, signs may not be seen for several hours. Asymptomatic animals may have emesis induced and activated charcoal administered. Fluid therapy is important to enhance elimination and maintain CV stability. Agitation, hyperactivity, and tremors tend to respond best to phenothiazines. For acepromazine and chlorpromazine, start at the low end of the dosage range and increase as needed. Diazepam can worsen dysphoria and is not recommended. Because part of the syndrome is related to serotonin excess, cyproheptadine (1.1 mg/kg PO or per rectum) has been used to manage some of the CNS effects. If tachycardia persists after institution of sedation, cyproheptadine and fluid therapy, propranolol may be used. Signs may persist up to 48-72 hrs in severe cases.

Baclofen

Baclofen is a centrally acting skeletal muscle relaxant that mimics γ-aminobutyric acid (GABA) within the spinal cord and causes a flaccid paralysis of skeletal muscles. At oral therapeutic levels, baclofen has virtually no CNS effects due to its poor ability to cross the blood brain barrier, but in overdose situations, CNS effects are common. The most common clinical signs of toxicosis are vomiting, ataxia and vocalization/disorientation, but the most life threatening signs are dyspnea, respiratory arrest and seizures. Dyspnea and respiratory arrest are secondary to paralysis of the diaphragm and intercostal muscles.

The onset of clinical signs varies in dogs with signs occurring anywhere from 15 minutes to 7 hours post exposure (average of 1.9 hr). Duration of clinical signs vary from several hours to several days. Signs can continue long after serum baclofen levels have returned to normal due to the slow clearance from the CNS. Dog doses as low as 1.3 mg/kg can cause vomiting, depression and vocalizing. There are no established lethal doses in animals, but per the APCC data base, deaths in dogs have occurred at doses as low as 8 mg/kg.

Due to the rapid onset of clinical signs, emesis should be considered in only the asymptomatic, recently exposed patient. Gastric lavage may be considered with large ingestions, but care must be taken to ensure that anesthesia does not compound CNS depression. Short acting induction agents such as propofol or pentothal followed by inhalent anesthesia with a protected airway is preferred. All asymptomatic cases should receive activated charcoal with a cathartic. Avoid magnesium-based cathartics (Epsom salts), as they may worsen CNS depression. Exposed animals should be monitored for 12 hours for development of clinical signs.

Ventilatory support is a prime concern and endotracheal intubation and positive pressure mechanical ventilatory support may be needed for an extended time in severe cases. Diazepam is the drug of choice for centrally acting skeletal muscle relaxant induced seizures. Propofol or isoflurane may be considered in cases that are refractory to diazepam. Long acting barbiturates or other agents that produce profound or prolonged CNS depression should be used with care. Cyproheptadine (1.1 mg/kg PO or rectally) has been used successfully to reduce the vocalization/disorientation seen in some animals. Fluid diuresis is used to enhance elimination and maintain blood pressure. Intralipids have been used successfully in early intoxications. The use of CNS respiratory stimulants are of questionable value and experimental studies have failed to consistently produce positive outcomes when flumazenil was used and have potential to cause serious adverse effects (seizures). Prognosis is variable, and can depend on the availability of ventilatory support for depressed patients. Prognosis is more guarded if seizures develop.

Calcium Channel Blockers (CCB)

Calcium channel blockers (verapamil, diltiazem, nifedipine, etc.) slow the activity of the SA pacemaker as well as conduction through the AV node. They also cause frequency-dependent channel blockade in the AV node so that it is effective in slowing supraventricular arrhythmias. Calcium channel blockers reduce total peripheral resistance, blood pressure, and cardiac afterload. They can also cause negative inotropic effects, but this is rarely of clinical significance.

Calcium channel blockers have a low margin of safety, causing hypotension and dysrhythmias. Bradycardia is the most common arrhythmias although others are possible. Hyperglycemia, hyperkalemia, hypokalemia, and hypocalcemia are possible. Standard decontamination practices should be performed in cases of significant exposure. Any dose exceeding the therapeutic dose should be monitored for cardiovascular signs and electrolyte abnormalities. Fluid replacement and calcium administration may help correct blood pressure and conduction abnormalities. Atropine and isoproterenol may be used for bradyarrhythmias and may be more effective following calcium administration. If hypotension persists, insulin/dextrose, norepinephrine, neosynephrine, dopamine, dobutamine, or amrinone can be tried. The newest treatment is intralipids. Prognosis is dependent on dosage and response to therapy.

Digoxin

Digoxin is a digitalis glycoside that can be found in elixers (0.05 and 0. 15 mg/ml), tablets (0. 125, 0.25 and 0.5 mg) and capsules (0.05, 0.1 and 0.2 mg). Digitalis inhibits the myocardial cell membrane Na-K ATPase pump. This inhibition results in increased intracellular sodium concentrations. The sodium must exit by exchanging with extracellular calcium. The sarcoplasmic reticulum binds the excess calcium and uses it to increase contractility. Digitalis is used in the treatment of congestive heart failure, atrial fibrillation or flutter and supraventricular tachycardias.

Absorption following oral administration occurs in the small intestine and is variable dependent on the oral dosage form used. Food may delay, but does not alter, the extent of absorption. Peak cardiac effects are seen in 6-8 hours. Digoxin is distributed widely throughout the body with highest levels found in kidneys, heart, intestine, stomach, liver and skeletal muscle. The half life of digoxin is 14.4 - 56 hours in the dog and 23.8 – 42.8 hours in the cat.

Adverse effects of digitalis glycosides are usually associated with high or toxic serum levels and are categorized into cardiac and extracardiac signs and symptoms. Cardiac effects may include almost every type of arrhythmia described. The more common arrhythmias or ECG changes seen include: complete or incomplete heart block, bigeminy, ST segment changes, paroxysmal ventricular or atrial tachycardias with block, and multifocal PVCs. Extracardiac effects most commonly seen in veterinary medicine include mild GI upset, anorexia, weight loss, depression and diarrhea. Hyperkalemia and hyponatremia are seen with overdosage.

In dogs the acute toxic dose after IV administration has been reported to be 0.177 mg/kg. The minimum lethal dose of cardiac glycosides are not well established, but 0.33 mg/kg orally in a dog was lethal. Drug levels may be available from a human hospital on a "stat" basis. Cats are relatively sensitive to digoxin while dogs tend to be more tolerant of high serum levels. Therapeutic range for the dog is 0.9 - 3.0 ng/ml (<6.0 ng/ml is moderately toxic; >6.0 ng/ml is highly toxic). Therapeutic drug levels in the cat are 0.9 - 2.0 ng/ml.

Emesis can be induced with recent ingestion in an asymptomatic animal. Activated charcoal decreases digoxin absorption up to 96%. In the symptomatic patient supportive and symptomatic therapy should be implemented. IV fluids should be started at maintenance rate, but do not use calcium-containing fluids like Ringer's or LRS. Forced diuresis does not accelerate the elimination of cardiac glycosides and may worsen electrolyte imbalances. Serum electrolytes, arterial blood gases, and continuous ECG monitoring should be instituted. In severe intoxication, monitor serum potassium hourly.

The use of specific antiarrhythmic agents in treating life-threatening digitalis-induced arrhythmias may be necessary. Phenytoin and lidocaine are the drugs of choice for tachyarrhythmias because they reduce automaticity, disrupt re-entrant pathways and reduce sympathetic tone. Propranolol is the next choice as it blocks sympathetic nerve activity. Atropine may be used to treat sinus bradycardia, SA arrest, or 2nd or 3rd degree AV block. Digibind® (Burroughs Wellcome Co., Research Park Triangle, NC) is a specific antagonist to digoxin. It is an immune Fab produced from specific digoxin antibodies from sheep and will bind directly to the drug, inactivating it. It is expensive however and several vials may be needed for treatment. Prognosis is guarded with large ingestions especially in patients with underlying disease and risk factors.

Imidazoline decongestants

Naphazoline (Clear Eyes), tetrahydrozoline, oxymetazoline (Afrin), and xylometazoline (Neo-Synephrine) are imidazoline decongestants. They are vasoconstrictors used for the symptomatic relief of rhinitis, sinusitis, or conjunctival inflammation. Imidazolines are sympathomimetic agents with primary effect on alpha-adrenergic receptors. There is little if any effect on beta-adrenergic receptors. Overdose or intoxication from oral ingestion or excessive topical administration can result in severe drowsiness with diaphoresis, hypotension or shock, bradycardia, respiratory depression, and coma.

Imidazoline decongestants are readily absorbed via the gastrointestinal tract. Most cases result when a dog punctures or chews a container and ingests the contents. Signs of intoxication may include (with decreasing frequency): vomiting, bradycardia, cardiac arrhythmias, poor capillary refill time, hypotension or hypertension, panting, upper respiratory sounds, depression/weakness/drowsiness, nervousness, hyperactivity and shaking. These signs are expected to be present within 30 minutes to 4 hours post exposure.

Emesis is generally not practical due to very rapid absorption and onset of clinical signs. Monitor heart rate and level of alertness. If no signs within 3-4 hours, do not expect to see any. Assess heart rate, rhythm and blood pressure and consider EKG if indicated. Administer intravenous fluids. If there is a significant decrease in heart rate, give atropine at a pre-anesthetic dose. Atropine may not raise the heart rate, but its use was followed by a significant rise in blood pressure. Give diazepam if significant nervous effects (apprehension, anxiousness, shaking) are present. If signs persist for several hours, assess serum electrolytes (potassium, sodium, chloride) and correct them as needed. Since this is an alpha-adrenergic agent, it is reasonable to consider using an alpha antagonist like yohimbine or atipamezole to reverse the hypotension and bradycardia.

5-Fluorouracil

5-Fluorouracil (5-FU) is in the antimetabolite class of antineoplastic agents. The topical creams and topical solutions (Efudex, Fluoroplex, Adrucil) are extremely toxic if ingested. 5-FU destroys rapidly dividing cells, causing severe vomiting and GI irritation. It is likely converted to fluorocitrate affecting the Krebs cycle and causing seizures just as fluoroacetate. If given enough time (5-20 days) and if the animal survives, it could destroy bone marrow stem cells resulting in leukopenia which can progress to a pancytopenia. This may be because the 5-FU metabolite, FdUMP, does not readily diffuse across cell membranes as 5-FU does leading to delayed clearance from the bone marrow.

The onset of clinical signs usually occurred within 0.5 to 5 hours following ingestion. 5-FU rapidly distributes to the total body water and it is absorbed by all cells. In dogs that survived, signs lasted from 18 hours to 14 days. In dogs that died, signs lasted from 1.5 hours to 6 days. The minimum lethal oral dose for the dog is 20 mg/kg, but signs of toxicity are seen as low as 8.6 mg/kg.

Often signs begin with vomiting and progress to tremors and seizures within a few hours. The vomiting isn't always seen before seizures, nor are seizures seen in every case. Seizures may require care for more than 24 hours. Can also cause cardiac arrest. Most common clinical signs in dogs in decending order are seizures, vomiting (with or without blood), death/euthanasia (only 1 of 22 dogs lived at doses above 83 mg/kg), lethargy, respiratory distress, tremors, cardiac arrhythmias, hypersalivation, ataxia, disorientation, and diarrhea (with or without blood).

Emesis, activated charcoal and cathartic can be started if the animal is asymptomatic and the ingestion was recent (less than 1 hour). Seizures and tremors are rarely controlled with diazepam. Pentobarbitol, phenobarbitol, gas anesthetics (isoflurane), and propofol have been used successfully. GI protectants should be started. The use of metoclopramide in cases of protracted vomiting has been suggested. Metoclopramide must be used with care as it could cause additional neurologic signs and there are drug interactions. IV fluids, thermoregulation, antibiotics, and pain control are very important parts of the therapy.

Lesions on necropsy include hemorragic colitis, gastrointestinal mucosal ulceration (from stomach to colon), desquamation of the gastrointestinal tract, stomatitis, myocardial ischemia, pulmonary edema, and congestion of the lungs, liver, thymus, kidneys, and small intestine.

If animals live through the severe vomiting and seizures, WBC's could start to decline in 5-20 days. Filgrastim (Neupogen) may be given for neutropenia (5-6 mg/kg SQ). Prognosis is guarded to poor once signs occur. Sixty-four percent of dogs ingesting 5-FU die or are euthanized.

Flucytosine is an antifungal agent that must be converted to 5-FU by cytosine deaminase to have cytotoxic effects. Mammalian cells lack cytosine deaminase, however, if taken orally, microbes in the GI tract will convert Flucytosine to 5-FU and could result in a toxicity.

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